Is activation of the renin-angiotensin system hazardous to your health?

This editorial refers to ‘Plasma renin activity predicts cardiovascular mortality in the Heart Outcomes Prevention Evaluation (HOPE) study’†, by S. Verma et al., on page 2135 Representing the renin–angiotensin system (RAS) as a villain contributing to cardiovascular morbid events has become a popular theme in recent years. This storyline has helped to explain the benefit of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in hypertension, myocardial infarction, heart failure, and atherosclerosis, and is supported by a rich array of trial data demonstrating that RAS activity is a predictor of adverse events. The story has been further enhanced by experimental data demonstrating that angiotensin exerts adverse effects on the heart and blood vessels that could account for the relationship between RAS activity and morbidity and mortality. On its face, therefore, the report by Verma et al.1 merely expands that simple theme with another and somewhat unique population that had not previously been studied in this context. But is the story as simple and straight forward as we would like to think? Plasma renin activity (PRA) measurement as a guide to activity of the RAS and as a surrogate for angiotensin levels was popularized in the 1970s as a means of exploring the mechanisms of hypertension. Physiologically, of course, renin activity and angiotensin function to preserve sodium by enhancing renal sodium reabsorption. Low salt diets stimulate RAS activation, as does the upright posture. The systemic vasoconstrictor effect of this activation thus is designed to support blood pressure in the face of a decline in cardiac output induced by volume or sodium depletion. The observation that PRA varies among individuals, independent of sodium consumption and excretion, led to speculation that this variability, whether genetic or environmental, might play a role in the development of hypertension.2 Furthermore, Laragh et al. concluded that hypertension could be categorized by variation in the balance between renin activity and sodium excretion.3 They proposed that renin profiling could serve to guide pharmacotherapy, which by that time included drugs that could inhibit the RAS. They further observed that high renin activity was associated with future morbid events such as myocardial infarction.4 The ‘elephant in the room’ in this attractive hypothesis was that renin activity, and presumably angiotensin levels, were considerably higher in response to sodium restriction and diuretics than in those individuals whose resting levels identified them as ‘high renin’. If physiological perturbations produce high PRA levels without adverse consequences, how can modest increases account for the morbidity claimed to be associated with RAS activation? It was clearly more than the levels themselves and might be attributed to an interaction with other factors, including probably sodium. Our initial interest in the role of the RAS system in heart failure was motivated by our search for a mechanism and potential therapeutic target for the systemic vasoconstriction that was increasing impedance to left ventricular emptying and reducing cardiac output.5 The favourable haemodynamic response to ACE inhibitors, and subsequently ARBs and direct renin inhibitors (DRIs), certainly supports the concept that angiotensin is a contributor to that vasoconstriction. Indeed, the magnitude of the acute haemodynamic response to these inhibitors is directly related to PRA levels.6 Recent emphasis has shifted, however, from the acute functional effect of these drugs on the tone of the vasculature to their long-term structural influences on the arteries and myocardium. The benefit of ACE inhibitors and ARBs on outcomes in heart failure, atherosclerosis, and in the post-myocardial infarction period cannot be attributed to blood pressure lowering. It must be related to structural benefits of these inhibitors of the RAS, quite independent from their actions to relax the vasculature.7 Are these benefits dependent on activation of the RAS? In these pre-ACE inhibitor era studies, PRA levels were modestly predictive of mortality in heart failure, but this predictive value disappeared when corrected for plasma norepinephrine levels.8 If the benefit of RAS inhibitors is dependent on activation of the RAS, then shouldn't we be measuring PRA, or more specifically plasma angiotensin levels, as a guide to therapy? Such an approach has never gained popularity, perhaps appropriately so. The multiple drugs used today to treat cardiovascular diseases have so many discordant effects on components of the RAS that it would seem hopeless to utilize a single measurement of one of these components to plan a therapeutic regimen (Figure 1). Some agents suppress and some stimulate PRA, and the relationship between PRA and angiotensin becomes hopelessly distorted in the presence of ACE inhibitors. Unfortunately, measurement of plasma angiotensin is a laborious procedure requiring meticulous collection and analytical techniques not suitable for the clinical environment. Even if one could measure the hormone levels accurately, however, the widespread use of ARBs would eliminate the direct relationship between hormone levels and receptor activation. Furthermore, the structural benefits of these drugs seem not to be dependent on the activity of the RAS. The conventional wisdom is that they work in everyone, perhaps regardless of PRA, angiotensin levels, or receptor activation. Influence of drugs on the renin–angiotensin–aldosterone system. β-Blockers and direct renin inhibitors interfere with formation of angiotensin I, angiotensin-converting enzyme (ACE) inhibitors interfere with angiotensin II formation, and angiotensin receptor blockers (ARBs) interfere with AT1 receptor activation. Inhibition of AT1 receptor activation, whether by reducing angiotensin II levels or by blocking the receptor, stimulates renin activity (PRA). This renin stimulation may increase levels of the hormones proximal to the site of the blocker. AT1 activation stimulates aldosterone release and promotes vasoconstriction and structural remodelling, which may also be promoted by aldosterone. The relationship between morbid events and PRA in atherosclerosis, as identified in the HOPE analysis of Verma et al.,1 as well as the demonstration of the predictive value of PRA for morbid events in heart failure in the recent Val-HeFT analysis by Masson et al.9 must therefore be interpreted in context. The relationship between PRA and adverse outcomes was retained despite the frequent use in these studies of drugs that alter PRA and the relationship between PRA and RAS activity. In addition, the relationship between PRA and outcomes was not apparently influenced by randomization to placebo or study drug (either an ACE inhibitor or an ARB). Is it that these confounding influences are too small to overwhelm the fundamental truth of RAS activation and adverse outcomes? Is PRA a marker for a bad outcome that is not responsive to inhibition of the RAS? Or are the data telling us something we cannot yet fully understand? Verma et al. conclude that PRA is a ‘risk marker and potential target for therapy’ in atherosclerosis. The implication that these population data demonstrating a small but statistically significant relationship of PRA with outcome can be used as a guide to treatment of individuals with a similar disease is highly suspect. Hazard ratios of 1.5–1.9 based on a 5-fold difference in PRA, which are uncorrected for the influence of co-therapy, provide no justification for individual therapeutic decision-making, especially because such decisions are always binary. Furthermore, nothing in the data leads us to conclude that RAS inhibitors would counteract the apparent adverse influence of PRA on outcome. Despite copious data from well-designed large-scale trials we still do not know how to use measures of RAS activity to help steer management of cardiovascular diseases. Conflict of interest: none declared.